1. Field Of The Invention
This invention relates to a pharmaceutical composition for use in the treatment of cerebral edema. More particularly, the present invention relates to a pharmaceutical composition containing a peptide having anti-cerebral edema activity. The pharmaceutical composition of the present invention can advantageously be used not only as a medicine for the treatment of cerebral edema, but also as a medicine for the prevention of cerebral edema.
2. Discussion Of Related Art
Cerebral edema is a symptom defined as an excessive accumulation of water in a brain tissue, which is caused by various brain injuries. Cerebral edema accompanies an increase in intracranial pressure. In more serious cases, cerebral edema itself functions to increase the intracranial pressure. The mechanism of the occurrence of cerebral edema varies according to the type of brain injury. Klatzo defined two types of cerebral edemas. One type is vasogenic edema which is caused by the transfer of water into a brain tissue, which water is leaked out of a blood-brain barrier, simultaneously with the leakage of a serum protein from the blood-brain barrier due to the damage thereof. The other type is cytotoxic edema which is caused by the water retained in a brain tissue due to the inhibition of the transfer of ions between the inside and the outside of the cell membrane of a brain tissue, which inhibition accompanies the metabolic inhibition of a brain tissue cell [Klatzo, I., "Neuropathological aspects of brain edema", J. Neuropath. Exp. Neurol., 26, 1-14(1967)]. According to clinical observation, most of the cerebral edemas are vasogenic edemas, while cytotoxic edema accompanies limited types of diseases, such as cerebral ischemia at a primary stage thereof, water poisoning and meningitis purulenta. Further, Fishman reported another type of cerebral edema, that is, interstitial edema which is caused by the reservation of cerebrospinal fluid in a cerebral medulla surrounding the cerebral venticles, ascribed to hydrocephalus [Fishman, R.A., "Brain edema", New Eng. J. Med., 293, 706 (1975)].
Heretofore, with respect to the treatment of cerebral edema, it has generally been attempted to remove water from a brain tissue on one hand and block intracranial pressure-increasing factors on the other. In this attempt, a surgical method and a pharmaceutical method are employed. In the surgical method, water is removed from a brain tissue so that the intracranial pressure can be reduced. As the pharmaceutical method, there can be mentioned, for example, a method in which a hypertonic solution, such as a glycerol solution, is administered. In this method, excess water in a brain tissue and other tissues is drawn out into a blood, followed by excretion as urine by the osmotic diuresis action of the hypertonic solution. Further, a steroid therapy and a barbital therapy can be mentioned as a therapeutic method for the treatment of cerebral edema. In the steroid therapy, a steroid is administered in a large amount in a short period so as to suppress the symptoms of cerebral edema. In the barbital method, barbital is administered for controlling the metabolism of a brain to thereby relieve the symptom. The administration of barbital is also effective to capture free radicals accumulated in the blood-brain barrier, which free radicals are likely to cause vasogenic edema, one type of cerebral edema, to thereby remove the cause of cerebral edema.
However, the above-mentioned conventional methods have various disadvantages. For example, the hypertonic solution method is disadvantageous in that the administration of a hypertonic solution for a long time causes abnormal homeostasis of water and electrolyte and there is a danger that when the administration is suspended, the intracranial pressure is temporarily increased as rebound phenomenon. Further, the steroid method is disadvantageous in that it has side effects, for example, hemorrhage in the digestive tract, susceptibility to infection, carbohydrate metabolic inhibition and the like. Moreover, the barbital method is disadvantageous in that the management of respiration of a patient at the time of the administration of barbital is difficult and that the hepatic insufficiency is likely to be caused when barbital is administered in a large amount.
On the other hand, in recent years, studies on atrial natriuretic peptide (hereinafter referred to as "ANP") which is a peptide derived from an atrium have been progressed, and various studies on the application of ANP have been made.
For example, a diuretic and an antihypertensive agent using ANP have been developed (Japanese Patent Application Laid-Open Specification No. 60-136596).
Further, Marc Cantin et al. determined the relationship between ANP and cyclic guanosine monophosphate (GMP), which acts as a messenger for the control of water content. They also found that ANP is capable of binding to various portions of the ciliary body of eyes. This fact suggests that ANP has a relation with the control of intraocular pressure and it can be used for treating a glaucoma [Marc Cantin and Jacques Genest, "The Heart as an Endocrine Gland", Scientific American, 254, 62-67 (1986)]. Thereafter, it has been attempted to develop a pharmaceutical composition for the treatment of glaucoma, containing ANP as an active ingredient.
Furthermore, Marc Cantin et al. administered .sup.125 I-ANP to a rat through a carotid artery and examined the brain of the rat by radioautography. As a result, it was found that .sup.125 I-ANP-binding site is present in the epithelial cells of the choroid plexus of each of the third cerebral venticle, the fourth cerebral venticle and the lateral venticle. At that time, it was already known that a cerebrospinal fluid is produced mainly in the choroid plexus. Based on these findings, they suggested that ANP controls the production of a cerebrospinal fluid [Bianchi, C., Gutkowska, J., Ballak, M., Thibault, G., Garcia, R., Genest, G., Cantin M., "Radioautographic Localization of .sup.125 I-Atrial Natriuretic Factor Biding Sites in the Brain", Neuro-endocrinology, 44, 365-372(1986)].
Further, Nathanson et al. found that when ANP is added to the epithelial cells of the choroid plexus isolated from a rabbit, which cells are capable of producing a cerebrospinal fluid, the amount of an intracellular cyclic GMP is increased. From this finding, they considered that the epithelium of the choroid plexus is a target organ of ANP and the ANP affects the secretory function of the epithelial cells. They also found that the intraventicular administration of ANP is effective for inhibiting the production of a cerebrospinal fluid. Thus, they substantiated the hypothesis of Marc Cantin et al. with respect to the activity of ANP for controlling the cerebrospinal fluid production. From these findings, they suggested that ANP can be used for treating hydrocephalus which is caused by the insufficiencies of the cerebrospinal fluid circulation system [Steardo, L., and Nathanson, J.A., "Brain Barrier Tissues: End Organs for Atriopeptins", Science, 235, 470-473(1987)].
As described above, the activity of ANP for controlling the cerebrospinal fluid production has already been known and the effectiveness of the use of ANP for the treatment of glaucoma, hydrocephalus, etc. has been suggested. However, it has not yet been suggested that ANP is effective for relieving the symptom of cerebral edema which is caused by various mechanisms.